The Study to Help the AIDS Research Effort (SHARE) was funded by NIAID and NCI in 1983 to study the natural history of infection with human immunodeficiency virus, type 1 (HIV). SHARE, along with similar sites in Chicago, Pittsburgh, and Los Angeles, forms the Multicenter AIDS Cohort Study (MACS). MACS participants, including 1447 enrolled in SHARE, have been followed semiannually since 1984 and have provided questionnaire data, physical exam data, laboratory data (including HIV serostatus and T-cell subset measurements), and a large repository of plasma, serum, cryopreserved peripheral blood mononuclear cells and other specimens. Evaluating and following the prevalent and incident cases of HIV-infection in SHARE and the MACS, has provided key insights into risk factors for infection with HIV-1, monitoring and mechanisms of progression of HIV infection once it is established, host defense against HIV, genetic factors affecting HIV pathogenesis, and use and efficacy of different therapies for HIV infection and for opportunistic pathogens. SHARE and MACS have just completed the recruitment of 1326 additional participants, including 352 in SHARE, who are younger and more non-Caucasian than the cohort previously recruited. This application requests the continuation of the followup of the SHARE cohort from 2004 to 2008. Expected survival and continuation in the study of HIV-infected cohort members through this time period is 88%. Specific Aims of the renewal include: determine the long-term effectiveness of highly active antiretroviral therapy (HAART);define determinants of individual responses to HAART including host genetic characteristics, co-infections (hepatitis viruses, HHV-8), immune responses to HIV, adherence, race/ethnicity;define mechanisms of host resistance to HIV infection and progression of the infection;and serve as a platform for independently funded pathogenesis studies and other collaborative research, including virological and immunological mechanisms of HIV-1 pathogenesis, laboratory correlates of disease progression or non-progression, and biological interactions between co-infections and HIV. These aims can be addressed only with continued followup of this extremely well-characterized cohort. SHARE and the MACS should continue to play a leading role in studies designed to lead to better treatments and preventive vaccines for HIV infection.